The disorders of xanthohistiocytic proliferation involving histiocytes, foam cells, and mixed inflammatory cells are divided into Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH).
LCH is an idiopathic spectrum of disorders characterized by a clonal proliferation of abnormal cells phenotypically similar to Langerhans cells of the skin. Clinically, LCH is characterized by lytic bony lesions and cutaneous findings that range from soft tissue swelling to eczema- and seborrheic dermatitis-like skin changes and ulceration.
INSIGHT 
Histiocytosis can be extremely difficult to diagnose. In infants with diaper rash that will not heal, particularly if there are erosions in the folds or petechiae/purpura, histiocytosis should be considered.
SYNONYMS Class I histiocytosis, nonlipid reticuloendotheliosis, eosinophilic granulomatosis. Previously termed Histiocytosis X.
In recent years, a concerted effort has been made to aggregate subforms of the disease under the single disease term LCH, given overlap in clinical and pathophysiologic feature. Prior classification approaches distinguished between the following overlapping subtypes, which we present for historical reference:
Letterer–Siwe disease: an aggressive form of LCH with diffuse skin and organ infiltration and thrombocytopenia
Hand–Schüller–Christian disease: LCH with lytic skull lesions, exophthalmos, and diabetes insipidus
Eosinophilic granuloma: single osteolytic bony lesion ± skin/soft tissue lesion
Hashimoto–Pritzker disease: congenital self-healing reticulohistiocytosis.
Given the rarity of the disease, we encourage the single term LCH to encompass the spectrum of disease.
AGE Any age, most common 1 to 3 years.
GENDER M > F, 2:1.
INCIDENCE Rare, 3 to 5/million children.
GENETICS Familial case reports. Mutations in the BRAF oncogene have been seen in a large percentage of LCH lesions.
The proliferating Langerhans-like cell appears to be primarily responsible for the clinical manifestation of LCH. The stimulus for the proliferation may be a disturbance of intracellular lipid metabolism, a reactive response to infection (possible viral), a primary immunologic disorder of the host, or an inherited neoplastic disorder. Gene expression studies have demonstrated upregulation of factors associated with T-cell recruitment and stimulation in LCH, as well as growth factors including TGF-β.
LCH has a broad clinical spectrum, but in the most aggressive form, the infant appears systemically ill with a generalized skin eruption (seborrhea, petechiae, and purpura) followed by fever, anemia, thrombocytopenia, adenopathy, hepatosplenomegaly, and/or skeletal lesions, demonstrating multisystem involvement. Conversely, in cases of single-system LCH, the affected individual may be asymptomatic.
TYPE Papules, plaques, vesicles, scale, petechiae, purpura, ulceration, necrosis.
COLOR Pink, flesh-colored.
SIZE 1 to 2 mm up to 1 cm in size.
FEVER Lymphadenopathy (LAD). Ill appearance.
PULMONARY 10% of patients. Infiltrative disease of the lung upper and midzones, pneumothorax. Persistent cough.
LIVER Hepatosplenomegaly, transaminitis, clotting factor abnormalities.
BONE 75% of patients. Osteolytic lesions: calvarium, sphenoid bone, sella turcica, mandible, long bones of upper extremities (UEs), vertebrae.
OTHER Otitis media, diabetes insipidus/exophthalmos/bony lesions in previously classified Hand–Schüller–Christian variant.
The differential diagnosis of LCH based on skin manifestations is broad given the multiple cutaneous morphologies. The differential includes seborrhea, candidiasis, Darier disease, leukemia, lymphoma, multiple myeloma, urticaria pigmentosa (UP), mycosis fungoides (MF), and non-LCH.
HISTOPATHOLOGY Proliferation of Langerhans-like cells with distinct morphologic (pale eosinophilic cytoplasm, a kidney-shaped nucleus), ultrastructural (Birbeck granules), and immune-histochemical markers [CD1a+, langerin (CD207)+, ATPase+, S-100+, α-D-mannosidase+, peanut agglutinin+].
RADIOGRAPHIC FINDINGS Osteolytic lesion in calvarium, femur, rib, sphenoid, sella turcica, mandible, long bones of UEs. Chest: diffuse interstitial fibrosis in lung upper and midzones, pneumothorax; high-resolution chest CT demonstrates parenchymal cysts and nodules predominantly in the mid and upper lung zones.
The prognosis of LCH varies according to the extent of systemic involvement. Patients with single-system, unicentric disease have a relatively benign course with excellent prognosis. Patients older than 2 years at the time of diagnosis, without involvement of the hematopoietic system, liver, lungs, or spleen, have 100% probability of survival. However, given the possibility for disease reactivation, close follow-up is recommended (see Management below).
Patients with systemic involvement have a higher mortality rate, especially children diagnosed before age 2 years with liver, lungs, spleen, or hematopoietic involvement. Even with aggressive treatment, mortality ranges up to 66% in this population if there is not early response to treatment. Of note, patients with leukemia (acute lymphoblastic leukemia or acute nonlymphoblastic leukemia) or solid tumors may have an increased incidence of LCH and vice versa.
The management and treatment of LCH is dependent upon the severity and extent of involvement. Mild skin-only LCH can be treated with topical steroids, antibacterial agents, psoralen ultraviolet A (PUVA), topical nitrogen mustard. Diffuse skin disease has been treated with oral methotrexate or oral thalidomide. Localized bony lesions can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), intralesional steroids, curette with or without bony chip packing, or low-dose (300–600 rads) irradiation. Systemic chemotherapy may be warranted depending on the site of single bony lesions.
Multisystem LCH can be systemically treated with corticosteroids, vinblastine, methotrexate, or epipodophyllotoxin (etoposide). Failure to respond to treatment after 6 weeks of these drugs is a poor prognostic indicator. Even in responsive patients, there is a high (58%) rate of LCH reactivity. Reactive disease can be treated with additional chemotherapy regimens, etanercept, cyclosporine, 2-chlorodeoxyadenosine, or imatinib mesylate. Finally, in recalcitrant cases, bone marrow, stem cell liver or lung transplantation may be necessary. Given the rarity of the disease, enrolment in a clinical trial may provide patients with access to the latest therapeutic approaches and insights to the disease.
Non-LCH encompasses a spectrum of disorders with a benign, cutaneous self-resolving proliferation of mononuclear phagocytes other than Langerhans cells. Clinical forms include juvenile xanthogranulomas (JXGs), benign cephalic histiocytosis, generalized eruptive histiocytosis, and indeterminate cell histiocytosis, which may represent different expressions of the same pathologic process. Rare forms in the adult population include Erdheim Chester disease, Rosai Dorfman disease, and multicentric reticulohistiocytosis.
SYNONYM Non-X histiocytosis.
JXGs are common, benign, self-healing lesions of infancy and childhood characterized by one or several red to yellow papules and nodules on the skin and rarely in other organs.
SYNONYM Nevoxanthoendothelioma (a misnomer).
AGE Birth (15%) to before age 1 year (75%).
GENDER M > F, 1.5:1.
INCIDENCE Most common form histiocytosis.
ETIOLOGY Unclear. Possibly reactive granuloma to unknown cause.
The exact pathophysiology is unknown. Postulated mechanisms include a histiocytic proliferation to unknown traumatic or infectious stimulus.
Asymptomatic cutaneous JXGs are present at or soon after birth, may proliferate in number and size for 1 to 2 years, and then both cutaneous and visceral lesions involute spontaneously within 3 to 6 years.
TYPE Papules to nodules.
COLOR Red–brown (Fig. 19-3), transitioning to yellow quickly.
FIGURE 19-3
Juvenile xanthogranuloma
Solitary red-brown nodule on the arm of a small child.
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